Significance: Approximately 15 million Americans suffer from asthma, which leads to about 4000 deaths per year, and is responsible for estimated annual total direct and indirect costs of $56 billion. Despite the existing treatments for asthma, predominantly combinations of inhaled ?2-agonists and corticosteroids (CSs), there remains a significant unmet medical need for new therapies which address two key issues: 1) approximately 10% of patients are insensitive to current medicines; and 2) a significant number of patients (up to 50%) have adherence challenges with the inhaled drugs, due to inhaler misuse, lack of use and/or side-effects. There is compelling evidence implicating T-helper 2 (Th2) cells in asthma via: i) the induction and maintenance of inflammation and ii) the progression to the morphological changes associated with chronic disease. Also, there is growing published support that acidic mammalian chitinase (AMCase), a member of the chitinase family of hydrolases, contributes to the Th2-driven inflammatory responses, tissue injury and remodeling associated with diseases such as asthma. Hypothesis: We thus hypothesize that an oral AMCase inhibitor will alter the pattern of inflammation in CS-insensitive asthmatics, may augment the response to CSs in severe asthmatics and will also be effective in Th2-mediated asthma, as well as avoiding the adherence issues with inhaled medicines. Innovation: Our company (OncoArendi Therapeutics) initiated a Drug Discovery Program focused on developing potent and selective, orally active AMCase inhibitors for asthma and other Th2-associated diseases. After synthesizing and testing more than 500 compounds, we have selected a clinical candidate to progress into development for asthma. Our lead candidate OAT-889 is very selective, has high potency, excellent oral bioavailability in rodents, with long terminal half-life, low clearance and high volume of distribution, and activity in two standard models of asthma. In addition, OAT-889 has moderate plasma protein binding across species, no significant inhibition of CYP enzymes or hERG, and is negative in the Ames genotoxicity test. OAT-889 has first-in-class potential, with no known competition from other BioPharmaceutical companies. We propose to file an IND for this novel oral small molecule AMCase inhibitor as a critical step towards the clinical development of this innovative asset to treat moderate-to-severe asthma patients. The major goals of this Fast-track proposal are: Phase I. Specific Aim 1: Evaluate the effects of the clinical candidate, OAT-889, in a murine chronic model of asthma involving exposure to Aspergillus fumigatus, which is not sensitive to inhaled CSs. Phase II. Specific Aim 1: Translational medicine studies in human lung. Specific Aim 2: File an IND for OAT-889 after completing the standard IND-enabling studies. OAT-889 is the first of a new class of oral compounds, AMCase inhibitors, which have the potential to manage patients with moderate-to-severe asthma who are not adequately controlled by current medicines, while significantly improving treatment adherence compared to standard inhaled therapy.